| First Author | Carter MJ | Year | 2017 |
| Journal | Leukemia | Volume | 31 |
| Issue | 6 | Pages | 1423-1433 |
| PubMed ID | 27843137 | Mgi Jnum | J:241805 |
| Mgi Id | MGI:5903675 | Doi | 10.1038/leu.2016.333 |
| Citation | Carter MJ, et al. (2017) PI3Kdelta inhibition elicits anti-leukemic effects through Bim-dependent apoptosis. Leukemia 31(6):1423-1433 |
| abstractText | PI3Kdelta plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kdelta inhibitors (PI3Kdeltai) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kdeltai. Here we characterize the molecular mechanisms responsible for PI3Kdeltai-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kdeltai-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Emu-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kdeltai imparted significant therapeutic responses in Emu-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim-/- Emu-Tcl1 Tg leukemias demonstrated resistance to PI3Kdeltai-induced apoptosis were refractory to PI3Kdeltai in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kdeltai, both alone and in combination therapy regimes. |
